Human K562 cells are an erythroleukemic line that may serve as a model for globin gene expression in human erythroid cells. K562 cells produce all the globins with the exception of Beta-globin. This inability to produce Beta-globin could be due to a mutation in the structural gene itself, a cis-acting mutation, or may be due to the regulatory environment of the cells, a trans-acting mutation. We have attempted to distinguish between these two types of mutations, and to identify the sequences involved in the mutation. By using the technique of gene transfer we have been able to reproducibly transfer exogenous globin genes into K562 cells and to study the expression of these genes in the environment that the cell provides. From these experiments we have been able to establish that a trans-acting mutation is responsible for the failure of Beta-globin to express in K562 cells, and that the 700 base pairs 5' to the cap site of the Beta-globin is implicated in this muation; that either a respressor binds to this region or that an activator required to turn on Beta-globin is absent from K562 cells.